Liver & intrahepatic bile ducts
Other malignancies
Intrahepatic cholangiocarcinoma (small and large duct types)
Editorial Board Member: Monika Vyas, M.D.
Deputy Editor-in-Chief: Catherine E. Hagen, M.D.
Topic Completed: 23 August 2021
Minor changes: 7 September 2021
Copyright: 2002-2021, PathologyOutlines.com, Inc.
PubMed Search: Cholangiocarcinoma [title] liver "intrahepatic bile duct" pathology
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Frozen section description | Frozen section images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Vazzano J, Chen W. Intrahepatic cholangiocarcinoma (small and large duct types). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/livertumorcholangiocarcinoma.html. Accessed October 15th, 2021.
Definition / general
- Intrahepatic cholangiocarcinoma (iCCA) is a malignant intrahepatic epithelial neoplasm with biliary differentiation, arising in the liver periphery / proximal to the left and right hepatic ducts (WHO 2019)
- iCCA classification systems (Surg Pathol Clin 2018;11:403, Nat Rev Gastroenterol Hepatol 2020;17:557):
- Histologic features
- Small duct type versus large duct type (2 types have morphologic and molecular but not prognostic differences) (Am J Surg Pathol 2018;42:1334)
- Macroscopic growth pattern
- Mass forming
- Periductal infiltrating
- Intraductal
- Mixed growth patterns
- Cell of origin
- Stem cells residing in the canals of Hering
- Stem cells within peribiliary glands
- Histologic features
Essential features
- Nonencapsulated, white-tan and firm intrahepatic mass
- Glandular malignancy with various degrees of atypia and differentiation, infiltrating a dense fibrous stroma
- Exclusion of metastatic adenocarcinoma by review of the patient's clinical history and application of an appropriate immunohistochemistry panel
- Large duct type iCCA: often hilar masses, obstructive cholestasis; share risk factors with extrahepatic bile duct adenocarcinomas (primary sclerosing cholangitis [PSC], liver fluke infection)
- Small duct type iCCA: peripheral, larger liver masses; shares risk factors with hepatocellular carcinomas (viral hepatitis, nonbiliary cirrhosis)
Terminology
- Also known as peripheral cholangiocarcinoma and intrahepatic bile duct carcinoma
ICD coding
- ICD-10: C22.1 - intrahepatic bile duct carcinoma
Epidemiology
- In the United States, the average annual incidence is 1.6 per 100,000/year (Cancer Control 2017;24:1073274817729245)
- 15% of primary liver malignancies worldwide
- Second most common malignancy arising from the liver
- 3% of all cases of gastrointestinal cancer
- ~10% of all bile duct carcinomas
- More common in East Asia, due to endemic liver fluke infection
- Most patients are aged between 55 and 75 years (Cancer Lett 2016;379:198)
- M > F (Cancer Lett 2016;379:198)
Pathophysiology
- Chronic inflammation of the intrahepatic bile ducts with sustained IL6-STAT3 signaling (Nat Rev Gastroenterol Hepatol 2020;17:557)
- IDH, EPHA2 and BAP1 mutations and FGFR2 fusions in iCCA; in contrast to PRKACA and PRKACB fusions, ELF3 and ARID1B mutations in extrahepatic tumors (Nat Genet 2015;47:1003)
- TP53 and SMAD4 mutations
- CpG island hypermethylation are more frequent in liver fluke associated cholangiocarcinoma
Etiology
- Common underlying risk factor: chronic inflammation of the biliary epithelium and bile stasis (Liver Int 2019;39:19)
- Small duct type iCCA:
- Nonbiliary cirrhosis: independent risk factor (Cancer Control 2017;24:1073274817729245)
- Alcoholic steatohepatitis / nonalcoholic steatohepatitis (NASH)
- Hepatitis B / hepatitis C (Cancer Control 2017;24:1073274817729245)
- Large duct type iCCA:
- Primary sclerosing cholangitis: 5 - 20% lifetime risk of developing cholangiocarcinoma (Cancer Control 2017;24:1073274817729245)
- Hepatobiliary parasites: Opisthorchis viverrini, Clonorchis sinensis
- Hepatolithiasis: more common in Southeast Asia and associated with an increased risk of 6 - 50 times
- Caroli disease: a congenital disorder characterized by multifocal, segmental dilatation of large intrahepatic bile ducts
- Choledochal cysts (types I and IV)
- Multiple bile duct hamartomas (von Meyenburg complexes) (Eur J Gastroenterol Hepatol 2009;21:580)
- Thorotrast: a colloidal suspension of thorium dioxide that was used as an intravascular contrast agent until the 1950s, with an increased risk of 300 times (Jarnagin: Blumgart's Surgery of the Liver, Biliary Tract and Pancreas, Volume 1, 6th Edition, 2016)
Diagrams / tables
Images hosted on other servers:
Classifications of
cholangiocarcinoma
Clinical features
- Asymptomatic in early stages (Nat Rev Clin Oncol 2018;15:95)
- Nonspecific symptoms in late stages, such as abdominal pain, malaise, fever, night sweats and weight loss / cachexia
- Jaundice / biliary obstruction are uncommon in iCCA, compared with extrahepatic cholangiocarcinoma
Diagnosis
- Clinicopathologic diagnosis by correlation of radiological, laboratory and surgical pathology findings
- Broad investigation of hepatic pathology and other malignancies should be conducted
- Colon cancer risk / screening history
- Alcohol consumption history
- Travel history (liver flukes)
- Viral hepatitis risk and serologies
- Autoimmune hepatitis serologies
- Iron studies (hemochromatosis), copper studies (Wilson disease)
- BMI (NASH)
- Exposure to hepatotoxins (thorotrast, aflatoxin)
- Labs
- CA 19-9, CEA, AFP
- In patients with PSC with or without ulcerative colitis, development of CCA can be predicted with CA 19-9 (a proposed cutoff level of 130 U/mL carries a sensitivity and specificity of 78.6% and 98.5% respectively
- Reference: Surg Oncol Clin N Am 2019;28:587, Surg Pathol Clin 2018;11:403
Laboratory
- Elevated serum CA 19-9
- Elevated serum CA 125
- Variably elevated serum alkaline phosphatase and bilirubin
- Reference: J Coll Physicians Surg Pak 2019;29:962
Radiology description
- Usually single, large, homogeneous mass with irregular margins on CT scan
- No pathognomonic CT / MRI features: may show progressive delayed enhancement, peripheral rim enhancement, subcapsular retraction
- Reference: Radiology 2018;288:7
Radiology images
Images hosted on other servers:
CT scan
Ultrasound
MRI
Prognostic factors
- Serum CEA, CA 19-9, tumor diameter and number, lymph node metastasis, vascular invasion and direct invasion and local extrahepatic metastasis are important prognostic factors (J Clin Oncol 2013;31:1188)
- Periductal infiltration and AJCC 8th edition pT stage (Am J Surg Pathol 2018;42:1334)
Case reports
- 38 year old pregnant woman with 1 week history of headache, nausea, vomiting and right upper abdominal pain (Case Reports Hepatol 2018;2018:6939747)
- 45 year old Thai man with 3 month history of right upper abdominal pain (Case Rep Surg 2018;2018:3862575)
- 58 year old woman with abdominal pain and jaundice (Medicine (Baltimore) 2018;97:e11015)
- 67 year old woman with chest pain and a lung nodule (Am J Case Rep 2018;19:35)
- 70 year old man with mass forming tumor with portal vein and bile duct thrombus (Int J Surg Case Rep 2017;40:13)
Treatment
- Surgical resection of the tumor is the potential curative therapy
- Frequently inoperable, often recur after surgery
- First line treatment for locally advanced or metastatic disease is gemcitabine / cisplatin
- Molecular testing recommended by National Comprehensive Cancer Network (NCCN) for unresectable and metastatic tumors (> 50% of NGS tested subjects have potentially actionable mutations)
- Ongoing clinical trials of targeted therapy: immune checkpoint inhibitors (anti-PD1, anti-PDL1, anti-CTLA4 antibodies), IDH1 inhibitors, AKT / PI3K / mTOR inhibitors, FGFR inhibitors and anti-EGFR and MEK inhibitors
- Reference: Surg Oncol Clin N Am 2019;28:587
Gross description
- Usually large, nonencapsulated, well demarcated, firm (due to desmoplastic reaction), white-tan to gray and nodular intrahepatic mass
- More frequent in the right lobe of the liver
- Satellite nodules are present in 30%
- Calcification is common
- Noncirrhotic background liver in most cases
- Grossly classified into 3 growth patterns (J Gastroenterol 2013;48:647):
- Mass forming: hepatic parenchymal solid mass
- Periductal infiltrating: infiltrates along the portal tracts, causing bile duct strictures
- Intraductal growth: papillary or polypoid growth inside a dilated bile duct
Gross images
Images hosted on other servers:
Mass forming cholangiocarcinomas
Periductal infiltrating cholangiocarcinoma
Frozen section description
- Margin status may be assessed via frozen section
- Invasive foci of cholangiocarcinoma are infiltrating glands found as direct stromal invasion, vessel invasion or perineural invasion
Frozen section images
Images hosted on other servers:
Invasive
cholangiocarcinoma
Microscopic (histologic) description
- iCCA consists of infiltrating well formed or cribriform glands in an abundant fibrous stroma (Liver Int 2019;39:7, Surg Pathol Clin 2018;11:403)
- Malignant glands are lined by cells with varying degrees of atypia and pleomorphism (Liver Int 2019;39:7)
- Usually well differentiated adenocarcinoma with mild atypia, intracytoplasmic lumina and intraluminal cellular debris; however, focal atypia with marked pleomorphism can also be present (Liver Int 2019;39:7)
- Commonly infiltrates between hepatic parenchymal cords at the periphery of the tumor
- Multicentricity and perineural invasion are common
- Histologic variants include mucinous, signet ring cell, clear cell, lymphoepithelioma-like, thyroid follicular-like, adenosquamous and sarcomatoid
- Small duct type iCCA (Liver Int 2019;39:7)
- Peripheral hepatic parenchyma
- Mass forming
- Cuboidal cells forming small tubular or anastomosing glands
- Variable lymphovascular / perineural invasion
- CD56, N-cadherin, CRP positive
- Subtypes include cholangiolocarcinoma, iCCA with ductal plate malformation-like pattern
- Large duct type iCCA (Liver Int 2019;39:7)
- Proximal to liver hilum
- Periductal infiltrating or mass forming
- Tall columnar cells that form large glands within open lumina; usually contain mucin
- BilIN, IPNB, ITPN are precursors
- Positive lymphovascular / perineural invasion
- MUC5AC, MUC6, S100P and TFF1 positive
Microscopic (histologic) images
Contributed by Wei Chen, M.D., Ph.D. and Omid Savari, M.D.
Large duct type iCCA
Small duct type iCCA
Anastomosing glands
Ductal plate malformation pattern
With necrosis
With sclerotic stroma
Irregular nuclear features
Infiltrating hepatic parenchyma
Poorly differentiated
Cytology description
- Isolated clusters and sheets of cuboidal or columnar cells with various degrees of nuclear enlargement and pleomorphism
- Wide range of glandular differentiation on cell block; > 10 proliferating ductules on FNA is helpful to differentiate cholangiocarcinoma from metastatic adenocarcinomas (Diagn Cytopathol 2000;22:359)
Cytology images
Images hosted on other servers:
Cholangiocarcinoma
on FNA
Positive stains
- CK7 (~90%), CK19 (80 - 90%), CK17, CAM 5.2, MOC31, EMA, monoclonal CEA, polyclonal CEA (diffuse cytoplasmic pattern), claudin4, pVHL (Indian J Pathol Microbiol 2018;61:2)
- Albumin RNA ISH (~80%) but does not differentiate iCCA from hepatocellular carcinoma (Ann Surg Oncol 2015;22:S1609, Am J Surg Pathol 2018;42:1334)
- Glypican 3 and HepPar1 occasionally positive in peripherally located iCCA
Negative stains
- CK20, TTF1, napsin A, ER (Indian J Pathol Microbiol 2018;61:2, Arch Pathol Lab Med 2003;127:1591)
- Progesterone receptor (PR) can be positive in cholangiocarcinoma (31%) (Arch Pathol Lab Med 2003;127:1591)
- GATA3 rarely positive (3%), seen in poorly differentiated iCCA (Appl Immunohistochem Mol Morphol 2020;28:460)
Molecular / cytogenetics description
- Mutations in KRAS (22%), BRAF (7%), EGFR (2%), IDH1 / IDH2 (14%), MET, activation of mTOR, overexpression of cyclin D1, overexpression of p21, inactivating mutations of DPC4 / SMAD4 (13 - 15%) and TP53 (15%) (BMC Cancer 2019;19:185)
- Chromosomal gains of 1q, 5p, 7p, 8q, 17q and 20q and losses of 1p, 4q, 8p, 9p, 17p and 18q (BMC Cancer 2019;19:185)
Sample pathology report
- Right lobe of liver, partial hepatectomy:
- Moderately differentiated adenocarcinoma, 6.5 cm, consistent with intrahepatic cholangiocarcinoma, small duct type
- Resection margins are negative for carcinoma
- Lymphovascular invasion present
- Metastatic adenocarcinoma involving 1 of 3 lymph nodes
- Pathologic TNM stage (AJCC 8th edition): pT2N1
- Background liver with mild steatosis and steatohepatitis; no advanced fibrosis
Differential diagnosis
- Metastatic adenocarcinoma:
- Immunohistochemistry and clinical history are helpful to rule out metastasis
- Hepatocellular carcinoma:
- Combined hepatocellular cholangiocarcinoma:
- Histologic evidence of both hepatocellular and biliary differentiation by H&E morphology and supported by immunohistochemistry (WHO 2019)
- Benign bile ductular reactions:
- Uniform growth pattern with lack of cytologic and architectural atypia and perineural invasion
- Epithelioid hemangioendothelioma:
- Bile duct adenoma:
- Small and well circumscribed, no or minimal cytologic atypia, lack of lymphovascular or perineural invasion
Additional references
- AJR Am J Roentgenol 2000;175:721, J Hepatobiliary Pancreat Sci 2015;22:101, Gut Liver 2017;11:13, Hepatobiliary Surg Nutr 2017;6:22, Hepatobiliary Pancreat Dis Int 2012;11:349, Onco Targets Ther 2017;10:1131, World J Gastrointest Oncol 2011;3:49, WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019
Board review style question #1
Which of the following is a feature of small duct type Intrahepatic cholangiocarcinoma (iCCA)?
- Arises from peribiliary glands
- Cuboidal cells forming small tubular or anastomosing glands
- Positive for S100P and TFF1 immunostains
- Tall columnar cell lined glands with luminal mucin production
Board review style answer #1
B. Cuboidal cells forming small tubular or anastomosing glands
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Reference: Intrahepatic cholangiocarcinoma (small and large duct types)
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Reference: Intrahepatic cholangiocarcinoma (small and large duct types)
Board review style question #2
Which of the following regarding intrahepatic cholangiocarcinoma (iCCA) risk factors is true?
- Alcoholic steatohepatitis / nonalcoholic steatohepatitis are risk factors for large duct type iCCA
- Biliary type cirrhosis is an independent risk factor for small duct type iCCA
- Chronic inflammation of the biliary epithelium is a common risk factor
- Primary sclerosing cholangitis is a risk factor for small duct type iCCA
Board review style answer #2
C. Chronic inflammation of the biliary epithelium is a common risk factor
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Reference: Intrahepatic cholangiocarcinoma (small and large duct types)
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Reference: Intrahepatic cholangiocarcinoma (small and large duct types)
